This project has the long-term goal of developing melanocortin receptor (MCR) antagonists as therapeutic drugs for cachexia. Cachexia, characterized by a lack of appetite and a loss of lean body mass, is a frequent complication of malignancy, infectious diseases, and chronic inflammatory states. The melanocortin system appears to play a crucial role in the regulation of food intake and energy homeostasis. There is clear experimental evidence supporting the utility of MCR antagonists in the treatment of cachexia produced by malignancies, infectious diseases, and radiation. However, there is also experimental and clinical evidence that MCR ligands have unacceptable cardiovascular effects. However, we have data that most, if not all, of the cardiovascular effects of MCR ligands are not due to interactions with known MCRs. Using structure-activity-analysis of MCR ligands with in vivo assays, we demonstrate the dissociation of melanocortin from cardiovascular activity. Our "concept" is that appropriate derivatives of MC ligands can suppress cardiovascular side- effects, while leaving desired therapeutic actions intact. The Specific Aims and Milestones of our Phase I project are;1. Design derivatives of MCR antagonists that suppress acute and chronic cardiovascular side- effects. Successful derivatives achieve Milestone #1. 2. Demonstrate that MCR antagonist derivatives with suppressed cardiovascular side-effects maintain anti-cachectic activity. Successful derivatives achieve Milestone #2. Achieving our Phase 1 milestones will demonstrate that we can increase the therapeutic index of MCR ligands, providing "proof of concept." Phase II of the project will involve the design and synthesis of centrally acting MCR antagonists to alleviate the metabolic sequelae of cachexia-inducing diseases. PUBLIC HEALTH RELEVANCE: Melanocortins (MCs) are naturally substances that have potential use as therapeutic agents in cachexia, a condition of reduced appetite with enhanced metabolic rate. However, MCs have unacceptable cardiovascular effects. We propose to develop MC drugs with reduced side-effects.